Liver Stem Cells and Transplantation

- Hepatic Stem Cells: In Search of

Although the ultimate application using hepatic/stem progenitorcells involves the development of an alternative therapy toliver transplantation for patients with liver failure, the prospectof this clinical reality remains in the future. There are currentlymore than 17,000 people on the waiting list for a liver transplant,with the majority of these patients suffering with cirrhosis,a manifestation of chronic liver injury (http://www.unos.org).In 2005, only approximately one-third of people waiting fora liver actually underwent a transplant [61]. Using hepatocytesor hepatic progenitor cells as cellular therapy to replace damagedlivers could potentially help alleviate some of the challengesin solid organ transplantation. Transplantation of mature hepatocytepopulations has been successfully performed in numerous experimentalmodels, but with less success in the clinical setting. Orenet al. transplanted mature rat hepatocytes into the portal systemof analbuminemic rats and restored serum albumin levels [62].The limited success with hepatocyte transplantation [63–66]involves the necessity to transplant large numbers of cellsto achieve acceptable function, as well as providing an outletfor biliary excretion.

Several studies have looked at the potential of stem/progenitorcells in transplantation [52, 67–69]. Sandhu et al. isolatedfetal liver epithelial progenitor cells and transplanted themin syngeneic dipeptidyl petidase IV mutant mice subjected tovarious liver injuries [18]. They found that the fetal liverepithelial progenitor cells, as opposed to the control groupof mature hepatocytes, continued to proliferate 6 months aftertransplantation. The fetal cells differentiated into cholangiocytesor hepatocytes depending on where they engrafted within therecipient liver. This is important, as mature hepatocytes donot form biliary structures [18], and one of the clinical challengesincludes engraftment of functional transplanted cells.

A concern about using hepatic progenitor cells for therapeutictransplantation is the link between oval cells and hepatocellularcarcinoma. An antigenic relationship between oval cells andhepatocellular carcinoma has been previously demonstrated. Inthe 1970s and 1980s, the oval cell was studied for its malignantpotential [70]. Primary hepatocellular carcinoma has been shownto express oval cell markers OV-6, OC-2, and OC-3 [71, 72].In addition, activation of the oval cell compartment occursprior to hepatocellular carcinoma development [73–75].One of the links between hepatocellular carcinoma and hepaticprogenitor cells is the ductular reaction that occurs with chronichepatitis. As the proliferative ability of the mature hepatocytefails, there is activation of a cell population in the intrahepaticbiliary tree that is thought to represent a potential stem cellcompartment [76]. Falkowski et al. also showed that this ductularreaction occurred with various forms of liver injury [77]. Inaddition, many of the phenotypic properties of hepatocellularcarcinomas are shared with hepatic progenitor cells, suggestinga common origin [76]. In addition to the carcinogenic potential,human liver stem cells have been implicated in several diseases,such as alcoholic liver disease and nonalcoholic fatty liverdisease. Roskams et al. present a good review of the role ofliver stem cells in various pathologies [78]. However, no definitivelink between adult or fetal hepatic progenitor cells and carcinomahas been clearly demonstrated. Perhaps this population of cellswill not have the same carcinogenic potential, but this is certainlyan area of research that will require further exploration.

Bioartificial liver (BAL) systems attempt to provide supportivefunction for a patient with liver disease while addressing theissue of malignant potential and immunologic reaction by creatinga barrier between the functioning hepatocytes and the patient.This field has been extensively studied over the past few decades,with several studies reaching preclinical trials as investigatorshave analyzed BAL design and cell source [79–83]. Parket al. present a concise review of BAL including the most recentstage III clinical trial. In the review, the authors point tothe current pitfalls associated with BAL [84]. Many of theseissues, such as cellular viability and xenografts, may be dealtwith by using species-specific stem cells.